Case Report MURCS Association with Partial …downloads.hindawi.com/journals/crig/2013/105052.pdfMURCS Association with Partial Duplication of the Distal Long Chromosome 5 and Unilateral

Hindawi Publishing CorporationCase Reports in GeneticsVolume 2013, Article ID 105052, 4 pageshttp://dx.doi.org/10.1155/2013/105052

Case ReportMURCS Association with Partial Duplication of the DistalLong Chromosome 5 and Unilateral Ovarian Agenesis

Anna Dabkowska-Huc,1 Piotr Skalba,1 and Antoni Pyrkosz2

1 Department of Gynecological Endocrinology, Medical University of Silesia, Medykow 14, 40-752 Katowice, Poland2Department of General and Molecular Biology and Genetics, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland

Correspondence should be addressed to Anna Dabkowska-Huc; [email protected]

Received 27 November 2012; Accepted 16 January 2013

Academic Editors: A. DeWan, P. Saccucci, and A. Sazci

Copyright © 2013 Anna Dabkowska-Huc et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

A combination of the congenital abnormalities, Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia, isdefined as the MURCS association. Various genetic defects have been described in the MURCS association so far, yet theunambiguous molecular basis of these disorders has not been established. We report the case of an 18-year-old woman whopresented with primary amenorrhea, right kidney, Arnold-Chiari malformation, and Klippel-Feil syndrome. In addition, thepatient showed the following unusual features: right ovarian and Skenes gland agenesis, cubitus valgus with hyperextension anddecreased range of motion at elbows, and facial changes. Moreover, the performed DNA analysis showed interstitial duplication inchromosome 5 (5q35.1). In the duplicated region, there are genes whose function is not well known. It is thought that they havean influence on the early stages of development and their joining in the later period can lead to neoplastic disorders, especiallyleukemias.

1. Background

MURCS association is the combined occurrence of thefollowing disorders: Mullerian duct aplasia, renal aplasia,and cervicothoracic somite dysplasia. Cervicothoracic somitedysplasia is described in Klippel-Feil syndrome (KFS).Changes in the relations in the base of the neck and headcan lead to the development of Arnold-Chiari malformation(ACM). ACM is a congenitalmalformation of the central ner-vous system, traditionally defined as downward herniation ofthe cerebellar tonsils through the foramen magnum [1].

In our case, in addition to the typical features, thefollowing abnormalities are unusual for MURCS association:right ovarian and Skenes gland agenesis, cubitus valgus withhyperextension and decreased range of motion at elbows,and changes in facial appearance [2–5]. MURCS girls arekaryotypically female (46, XX). Various genetic defects havebeen described in the MURCS association so far, yet theunambiguous molecular basis of these disorders has notbeen established [6, 7]. The relationship of 5q35.1 duplicationwith characteristic features for the MURCS association is

interesting. In the accessible literature, we have not found theconnection of this chromosomal duplication of 5q35.1 withMURCS association.

2. Case History

The 18-year-old patient was admitted to the GynecologicalEndocrinology Department because of primary amenorrhea(Figure 1).

Her height was 1.56m, weight 66 kg, BMI 27 kg/m2, andoccipitofrontal head circumference 59 cm (>97th percentile).She was born at term with hypotrophy. The facial featuresconsisted of a frontal bossing, a long and full face, withmiddlepart hypoplasia, and secondary prognathism, depressed andbroad nasal root, with long and fleshy nose, long philtrum,thick lips, low-set ear, and large ear lobes. Palate is high andnarrow. Neck is broad and short, secondary to cervical ver-tebral defects, with low hair line. Cervicothoracic vertebraldefects (Klippel-Feil malformation) and Sprengel scapularanomaly with probable torticollis in the infantile period, wereevident and induced a little face and thoracic asymmetry.

2 Case Reports in Genetics

Figure 1: The phenotype of the patient.

Thoracolumbar scoliosis with excessive lumbar lordosis isvisible. Trunk is clearly shorter than legs. Valgus elbows withhyperextension and decreased range of motion. Valgus knee,small feet with sandal gap and fifth toe clinodactyly; nails arehypoplastic.

Arnold-Chiari malformation type 1 was diagnosed in thepatient in the prenatal period. Klippel-Feil syndrome wasadditionally diagnosed in the period of childhood.

Examination and psychological testing showed averagemental development. The patient in addition to defects inthe cervical spine also shows abnormalities of the spine inthe thoracic and lumbar segments. The patient in childhoodwas found to have right kidney agenesis and a displaced leftkidney on the left side of the bladder with a wide, short ureter.Ureteral plastic surgery was performed at 2 years of age.

The physical examination revealed normal external gen-ital and breast development and normal development ofaxillary and pubic hair.

Gynecological examination showed oversized vaginallabia which hid the entrance to the vestibule of the vagina.There was no entrance to the Skenes gland on the right side.There was a complete vaginal and uterus atresia. Lack of theuterus and the right ovary was confirmed by ultrasound andmagnetic resonance imaging.

In the ultrasound examination, ectopic left kidney locatedon the left side of the bladder was found. Centrifugally inrelation to the left kidney was an ovary with one dominantfollicle and several small follicles. Urography confirmed thenormal secretory function of the left kidney and lack of a rightkidney.

Blood levels of ovarian and pituitary hormones weremostly correct.

The examination of karyotype with the GTG methodshowed a normal female karyotype. Because of existingdevelopmental disorders, we performed DNA analysis using

Figure 2: The genes located in the region of 5q35.1.

CGH microarray. Our results showed karyotype 46, XX,dup (5q35.1), interstitial duplication in chromosome 5 con-taining 914.2-973.3 kb (genome position HG18: 170405455-171328275). In the critical region by OMIM, there are fourgenes—RANBP17, TLX3,NPM1,and FGF18 and another geneMIR3912 (Figure 2). The examination was performed using135k NimbleGen CGX-12 chips.

In the duplicated region, including <1Mb, there are geneswhose function is not sufficiently known. Other anomaliesare associated with the duplication of the region 5q. One ofthem is a Boston type craniosynostosis. In 2005, Hunter et al.[8] describe the characteristics of the Hunter-McdAlpinesyndrome associated with the duplication of the region 5q35-qter. In our case, we have not identified those characteristics.The knowledge about them results mainly from the com-parison of conservative regions and observations on animalmodels. It is thought that they have an influence on the earlystages of development and their joining in the later periodmay lead to neoplastic disorders (Table 1).

Based on the above, on clinical judgment, the MURCSassociation with unique chromosomal rearrangement—duplication of chromosome 5q35.1—was diagnosed.

3. Discussion

TheMURCS association is remarkably variable and undoubt-edly causally heterogeneous. One must verify various chro-mosomal imbalances, and therefore a chromosome analysis,especially using the array-CGH method, is appropriate inmost cases. In addition to the broad variability of MURCSassociation, diagnosis may also be complicated by the exis-tence of several syndromes with overlapping features.

Oppelt et al. [6] reviewed 521 cases from the literature andfound 12 with MURCS association. Its incidence is 1 case per50,000 women [9]. SomeMURCS association cases belong tothe malformation spectrum of DiGeorge phenotype [10, 11].Hofstetter et al. [12] diagnosed a 16-year-old patient showingthe cardinal features of MURCS association accompanied bya persistent left superior vena cava and atrial septal defect,orofacial clefting, and mild reduction deformities of the lefthand.

Guerrier et al. [13] tried to find a candidate gene forMayer-Rokitansky-Kuster-Hauser syndrome, but they didnot divide the genes typical for MURCS. They explored thegene for galactose-1-phosphate uridyl transferase (GALT),the gene encoding the CFTR chloride channel, genes actingduring early development such as WT1 and PAX2, genes of

Case Reports in Genetics 3

Table 1: Action of genes in region 5q35.1. Based on OMIM 20/11/2012.

Genes in region 5q35.1 Action of genesTLX3 T-cell leukemia is caused by the defect of the geneRANBP17 Acute lymphoblastic leukemia is caused by the mutation of the geneNPM1 and ALK Fusion of these 2 genes can cause acute medullary leukemia

FGF18 Participates in oncogenesis; it also influences the differentiation of osteoblasts and chondrocytesand the development of cartilage forming from mesenchymal lung tissue

anti-Mullerian hormone or its receptor, and the hepatocytenuclear factor (HNF)-1𝛽 gene [14, 15]. But none showed anymutation and/or polymorphism associated with Mullerianaplasia.

The molecular basis of MURCS association remainsunknown. However, the molecular analysis of the similardisorder Mayer-Rokitansky-Kuster-Hauser syndrome madeby Ledig et al. revealed the candidate genes for this anomaly[16].

In our patient, interstitial duplication in chromosome 5(5q35.1) was diagnosed. This mutation was not connectedwith MURCS association previously. In the accessible liter-ature, we found a description of duplication in the region5q35.1 connected with the occurrence of the developmentaldisorders holoprosencephaly and preaxial polydactyly [17].

It is important to underline that the technique applied byus does not showwhich gene has the decisive influence on thephenotype observed in our patient.

Moreover, in our patient with the duplication of 5q35.1,gain-of-function genes exist in the critical region (partialtrisomy), not loss of function as in the above example.

The combination of abnormal ovarian development andMURCS association occurs extremely rarely. Al Kaissi et al.[11] reported a 17-year-old girl with MURCS association andovarian dysplasia. Tan et al. [18] described a patient withbicornuate uterus, right ovarian agenesis, unilateralmulticys-tic dysplastic kidneys, and other birth defects not typicallyassociated with MURCS. The present case deserves attentionbecause of many atypical findings and unparalleled chro-mosomal rearrangement. However, the association betweenthese conditions may be coincidental, and at present, thesetypes of ovarian pathology are not considered to be part ofthe MURCS clinical spectrum.

4. Conclusions

MURCS is a rare congenital disorder, and therefore difficult todiagnose.This case deserves attention because it also presentsunusual abnormalities and previously unreported interstitialduplication of chromosome 5q35.1, which may be associatedwith certain symptoms observed in the described patient.

The patient has given consent for the case report to bepublished.

Conflict of Interests

The authors declare that there is no conflict of interests.

References

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[10] M. Komura, Y. Kanamori, M. Sugiyama et al., “A female infantwho had both complete VACTERL association and MURCSassociation: report of a case,” Surgery Today, vol. 37, no. 10, pp.878–880, 2007.

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4 Case Reports in Genetics

[13] D. Guerrier, T. Mouchel, L. Pasquier, and I. Pellerin,“The Mayer-Rokitansky-Kuster-Hauser syndrome (congenitalabsence of uterus and vagina)—phenotypic manifestations andgenetic approaches,” Journal of Negative Results in BioMedicine,vol. 5, article 1, 2006.

[14] S. Klipstein, B. Bhagavath, C. Topipat, L. Sasur, R. H. Reindollar,and M. R. Gray, “The N314D polymorphism of the GALT geneis not associated with congenital absence of the uterus andvagina,” Molecular Human Reproduction, vol. 9, no. 3, pp. 171–174, 2003.

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[16] S. Ledig, C. Schippert, R. Strick, M. W. Beckmann, P. G.Oppelt, and P. Wieacker, “Recurrent aberrations identified byarray-CGH in patients with Mayer-Rokitansky-Kuster-Hausersyndrome,” Fertility and Sterility, vol. 95, no. 5, pp. 1589–1594,2011.

[17] D. A. Koolen, J. Herbergs, J. A. Veltman et al., “Holoprosen-cephaly and preaxial polydactyly associated with a 1.24 Mbduplication encompassing FBXW11 at 5q35.1,” Journal ofHumanGenetics, vol. 51, no. 8, pp. 721–726, 2006.

[18] T. Y. Tan, C. Whitelaw, and R. Savarirayan, “A patient withMullerian abnormalities, renal dysplasia, cervical spine fusion,cataracts and intellectual disability: MURCS-plus?” ClinicalDysmorphology, vol. 16, no. 4, pp. 271–273, 2007.

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Case Report MURCS Association with Partial …downloads.hindawi.com/journals/crig/2013/105052.pdfMURCS Association with Partial Duplication of the Distal Long Chromosome 5 and Unilateral